Cover Story

The Brain/Heart/Arteries Connections

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After the leaves had turned their million autumnal shades of red and yellow, but before the first snows had fallen, a study appeared in the pages of the journal Public Library of Science (PLOS) One.

It contained details on research being conducted by scientists at the Ottawa Heart Institute and the University of Maryland School of Medicine (UM SOM) – disclosing that they had uncovered a new pathway by which the brain uses an unusual steroid to control blood pressure. The study, which also suggests new approaches for treating high blood pressure and heart failure, could eventually lead to new treatments for hypertension and heart failure.

“This research gives us an entirely new way of understanding how the brain and the cardiovascular system work together,” said Dr. John Hamlyn, professor of physiology at the University of Maryland School of Medicine, one of the principal authors. “It opens a new and exciting way for us to work on innovative treatment approaches that could one day help patients.”

For decades, researchers have known that the brain controls the activity of the heart and the diameter of the peripheral arteries via the nervous system. Electrical impulses from the brain travel to the heart and the arteries via a network of nerves known as the sympathetic nervous system. This system is essential for daily life, but is often chronically over active in patients with high blood pressure or heart failure. In fact, many drugs that help with hypertension and heart failure work by decreasing the activity of the sympathetic nervous system. However, these drugs often have serious side effects, such as fatigue, dizziness, depression and erectile dysfunction.

“A lot of the medications we used in the past to block the sympathetic nervous system interfere with the acute regulation,” says Dr. Frans Leenen, Director of Hypertension at the Ottawa Heart Institute, and a principal author of the study. “These drawbacks have led to the search for novel ways to inhibit sympathetic nerve action while causing fewer problems for patients.”

Working with an animal model of hypertension, Dr. Leenen in collaboration with Dr. Hamlyn and Dr. Mordecai Blaustein, professor of physiology and medicine at the UM SOM, found a new link between the brain and increased blood pressure, namely, a little-known steroid called ouabain (pronounced WAH-bane).

This new study is the first to identify a particular pathway by which the brain regulates the diameter of the arteries via ouabain in the bloodstream, and causes an increase in contractile proteins in the arteries. This new humoral “chronic” pathway acts together with the more “acute” sympathetic nervous system pathway to control the function of arteries and thereby contributes to e.g. high blood pressure.

“Now that we understand the role of ouabain (EO), we can begin working on how to modify this new pathway to help people with cardiovascular problems,” said Dr. Blaustein. “The potential for this is big.” Dr. Blaustein, who has been doing research on the substance since 1977, said medications that block ouabain’s effects might improve the lives of people with hypertension and heart failure.

Dr. Leenen explains that there are new drugs being tested in clinical studies that can specifically block the Angiotensin II/EO effect in the brain. He says these newer drugs are just starting phase two. They basically prevent “that resetting in the brain of the sympathetic nervous system to a higher level, leaving the acute regulation intact. Once these drugs have been tried in healthy volunteers – the phase one trials are done and the drugs are determined safe, with no major side effects, one moves to what’s called phase two A studies – small scale studies in this case of people with high blood pressure. This development may not have come directly out of our study, but they are building on each other and that’s the way to look at it. I am actually collaborating with one of the discoverers of this new drug class,” says Leenen.

The research was funded by the Canadian Institutes of Health Research, the National Institutes of Health, and the University of Maryland School of Medicine. The paper, “Neuroendocrine Humoral and Vascular Components in the Pressor Pathway for Brain Angiotensin II: A New Axis in Long Term Blood Pressure Control,” is available on the The University of Ottawa Heart Institute (UOHI) website < www.ottawaheart.ca>, as is a video of Dr. Frans Leenen explaining the meaning of these recent findings.

The University of Ottawa Heart Institute is Canada’s largest and foremost heart health centre dedicated to understanding, treating and preventing heart disease. UOHI delivers high-tech care with a personal touch, shapes the way cardiovascular medicine is practised and revolutionizes cardiac treatment and understanding. It builds knowledge through research and translates discoveries into advanced care. UOHI serves the local, national and international community and is pioneering a new era in heart health.Heart Failure
“Digoxin is in the same chemical class as ouabain – but the body makes its own ouabain, whereas digoxin is a derivative of foxglove that has been used for I don’t know how many centuries. It’s used in heart failure to increase the activity of the heart – and get the blood pumping. It’s not much used anymore because it’s not that effective. We have better drugs now that regulate longer as well. That is a different situation though – high blood pressure than heart failure. Even if some of the mechanisms may be similar.”Chronic High Blood Pressure
“In the past, high blood pressure was a common cause of heart failure. Now this is much less common,” say Dr. Leenen. “Now heart failure is more due to heart attacks which destroy the heart muscle and that’s quite a different kind of thing. I rarely see anybody anymore with high blood pressure induced heart failure. In North America anyway – of course you can’t extrapolate that throughout the world.

“We have to come up with better strategies to prevent the blood pressure from going up in the first place. So this is separate from heart failure issues, because chronic high blood pressure results in a much broader consequence – and for that you really have to understand what the mechanisms are. And so in the past we would say whatever happens in the brain would be all about the sympathetic nervous system and the sympathetic nervous system is crucial for acute second-to-second regulation of your blood pressure in the biospheres of the brain that control the acute regulation of EO that’s crucial for survival or living. You have people who don’t have an effective sympathetic nervous system anymore and they can barely stand because the blood pressure would drop into their boots. When you stand up there’s a potent reflex that prevents the blood pressure from going down. So when you stand up you have to think about gravity impacting on your body and if nothing would happen, all the blood would pool in your legs.”